Acute kidney injury in COVID-19 pediatric patients in North America: Analysis of the virtual pediatric systems data

Background Despite extensive research into acute kidney injury (AKI) in adults, research into the epidemiology, associated risk factors, treatment, and mortality of AKI in pediatric COVID-19 patients is understudied. Advancing understanding of this disease is crucial to further developing treatment and preventative care strategies to reduce morbidity and mortality. Methods This is a retrospective analysis of 2,546 COVID-19 pediatric patients (age ≤ 21 years) who were admitted the ICU in North America. Analysis of the Virtual Pediatric Systems (VPS) COVID-19 database was conducted between January 1, 2020, and June 30, 2021. Results Out of a total of 2,546 COVID positive pediatric patients, 10.8% (n = 274) were diagnosed with AKI. Significantly higher continuous and categorical outcomes in the AKI subset compared to the non-AKI cohort included: length of stay at the hospital (LOS) [9.04 (5.11–16.66) vs. 5.09 (2.58–9.94) days], Pediatric Index of Mortality (PIM) 2 probability of death [1.20 (0.86–3.83) vs. 0.96 (0.79–1.72)], PIM 3 probability of death [0.98 (0.72–2.93) vs. 0.78 (0.69–1.26)], mortality [crude OR (95% CI): 5.01 (2.89–8.70)], airway and respiratory support [1.63 (1.27–2.10)], cardio-respiratory support [3.57 (1.55–8.23)], kidney support [12.52 (5.30–29.58)], and vascular access [4.84 (3.70–6.32)]. Conclusions This is one of the first large scale studies to analyze AKI among pediatric COVID-19 patients admitted to the ICU in North America. Although the course of the COVID-19 virus appears milder in the pediatric population, renal complications may result, increasing the risk of disease complication and mortality.


Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the 2019 coronavirus pandemic . According to The World Health Organization, over 182,319,261 cases and almost 4 million deaths have been reported worldwide as of July 2021 [1]. Kidney manifestations from COVID-19 are becoming increasingly prevalent, with acute kidney injury (AKI) contributing to high mortality rates. [2,3].

Study design and population
A retrospective analysis of 2,597 COVID-19 pediatric patients (age � 21 years) in the ICU within North America was performed by analyzing the VPS COVID-19 database, which includes data from over 200 pediatric critical care hospital units, between January 1, 2020 and June 30, 2021. Male and female patients <21 years old with AKI were analyzed (determined by Kidney Disease Improving Global Outcomes (KDIGO) staging of stage 1 or worse), along with patients with current or recent SARS-CoV-2 infection (determined by RT-PCR, serology, or antigen test), and ICU admission. Excluded from the study were patients >21 years old and patients with a negative SARS-CoV-2 status.
following variables were necessary: patient demographics (age, sex, race, ethnicity (White, Black, Hispanic, Asian/Pacific Islander, etc.), diagnosis (primary and secondary), lab order/ results (hematology and chemistry tests), image order/results, respiratory support modality, kidney replacement therapy modality (if utilized), medications, interventions and procedures, pediatric index of mortality (PIM) 2 and 3, discharge status, length of stay, and mortality. PIM 2 and 3 are severity scoring systems consisting of 10 variables which are used for predicting outcome of patients admitted to intensive care units (ICUs). It provides predicted % of mortality rate, where higher indicates greater probability of death [22]. The patients were separated into an AKI group and a non-AKI group. In the AKI group, patients were subcategorized based on staging of AKI severity by KDIGO guidelines. PIM3, KRT, and mortality data was used when urine output and serum creatinine level data were not available. If KRT was utilized, the patient was graded as AKI stage 2. Patients with the presence of mortality status were graded as AKI stage 3. The baseline parameters among AKI and non-AKI patients are provided in Table 1. The Pediatric Overall Performance Category (POPC) and the Pediatric Cerebral Performance Category (PCPC) scales are included as baseline parameters. Both the POPC and the PCP are qualitative assessments of performance, conducted by observers, based on the Glasgow Outcome Scale. Scores include 1 for good, 2 for mild disability, 3 for moderate disability, 4 for severe disability, and 5 for vegetative state or coma (6 indicates death, but was not included in the study) [23,24].
The laboratory profile of patients among the AKI and non-AKI group are included in Table 2. EGFR was calculated using IDMS-Traceable Schwartz Equation [eGFR = (0.41 x height in cm) � serum Cr]. Systolic and Diastolic blood pressure Z score was calculated using the equation provided in National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents [25]. In Table 1, BMI z score was calculated based upon the CDC's definition. Obesity is defined as BMI z score > 1.64 [18]. The association of different outcomes among AKI patients across different AKI stages are included in Table 4. The continuous outcome variables include hospital length of stay, PIM 2 probability of death and PIM 3 probability of death. Categorical outcomes include mortality, airway and respiratory support, cardiorespiratory support, kidney support, and vascular access. Vascular access included arterial catheter; Hemodialysis/ Plasmapheresis catheters; ECMO cannula; venous catheter (peripherally inserted central catheter; and percutaneous central venous catheter). Airway/respiratory support included endotracheal intubation (and duration of intubation); tracheostomy tube insertion (includes duration of intubation); invasive ventilation [mechanical ventilation, conventional (including CPAP plus pressure support); CPAP (invasive); HFOV (high frequency oscillator ventilation); Jet Ventilation]; Non-Invasive Respiratory Support or Ventilation [BiPAP (non-invasive); Mechanical Ventilation (Non-Invasive); CPAP (Non-Invasive); and Humidified High Flow Oxygen. Cardio-respiratory support included ECMO. Kidney support included Intermittent Hemodialysis (IHD).
This study has been approved by the Akron Children's Health Centers IRB Committee. The project approval number is 1632930-AKHC. This is a retrospective study of medical records, and the IRB committee waived the requirement for informed consent. All data was fully anonymized before being accessed.

Statistical analysis
All the variables were tested for normality using Kolmogorov-Smirnov test. Categorical variables were summarized as frequencies and percentages, while continuous variables were summarized as medians and inter-quartile range (IQR; 25th to 75th percentiles). Univariate analysis (using the chi-square or Fischer exact test for categorical variables and Mann Whitney U test for continuous variables) was carried out to assess the unadjusted relationship between the variables / different outcomes in the two groups. The multivariate linear or logistic regression was conducted to assess the association of different outcomes in the two groups after adjusting for variables observed to be significant in the univariate analysis. The difference in outcomes across three AKI staging group was assessed using Kruskal Wallis test for continuous variables and chi-square or Fischer exact test for categorical variables. A two-sided p value <0.05 was statistically significant. Statistical software (SPSS version 20) was used to perform the statistical analyses.
Clinical lab values which were higher in the AKI subset compared to the non-AKI cohort are reported as 'median (IQR)'and include: white blood cells count, serum potassium, blood urea nitrogen, creatinine, eGFR, and serum glucose. pH and bicarbonate levels were significantly lower in the AKI subset compared to the non-AKI cohort ( Table 2).
Significantly higher continuous and categorical outcomes in the AKI subset compared to the non-AKI cohort included: length of stay at the hospital (LOS) [  The mortality status and kidney support has been used in the classification of AKI stage; therefore these outcomes have not been considered for analysis (Table 4) A multivariate analysis for these outcomes based on AKI staging was not conducted due to the limited sample size.

Discussion
As of July 2021, the public, online VPS dashboard reported 2,596 pediatric patients with COVID-19 admitted to North American PICUs, of which approximately 3.04% required KRT. Within this subset, 86.4% were successfully discharged afterwards but 13.6% eventually died. From the patients that received KRT, 84.8% reported respiratory dysfunction, 81.2% reported circulatory dysfunction, and 42.4% reported vascular dysfunction. Notably, 14.0% of the total cohort reported kidney/urinary organ dysfunction, of which 88.8% were discharged and 11.2% died.
Among 2,546 COVID-19+ children, 10.8% of patients developed AKI. This coincides with the incidence reported by Derespina et al. in a study at New York City PICUs; Among 70 children admitted, 12.9% developed AKI [21]. Separate studies from Saudi Arabia, Iran, England, and France found much higher incidences of AKI at 21%, 22%, 29%, 19%, and 70% respectively [13,[15][16][17]26] (S1A Table in S1 File). Contrarily, studies from Italy, Spain, and two from China all reported AKI incidences significantly lower at 1.2%, 0.8%, 1.3%, and 2.7%, respectively [8,9,11,27] (S1A Table in S1 File). A recent study by Basu et al. reported an AKI incidence of 37.5% among 311 pediatric patients with COVID-19 [28]. However, only 51.4% of the patients had a confirmed SARS-CoV-2 infection, while the rest of the population were suspected cases. The authors acknowledge the presence of a possible selection bias, as provides may have been more likely to suspect SARS-CoV-2 with a negative test result in more severely ill patients than those who were less severely ill. Kari et al. hypothesized that some discrepancy between AKI incidences may also be attributed to differences in the AKI definitions used [13]. Some studies used the KDIGO definition to define AKI; however, an English study by Stewart et al. analyzed the British Association of Pediatric Nephrology's (BAPN) and found a higher incidence of 29% [26].
The VPS data showed that patients in the AKI group have a much higher rate of mortality [crude OR (95% CI): 5.01 (2.89-8.70)]. Likewise, a study from Saudi Arabia found a mortality rate of 42% among AKI patients and 0% among non-AKI patients [13]. The VPS results deviate from Bjornstad et al's multicenter study throughout the United States, Eastern Europe, and Russia, where a mortality rate of 6% was found among AKI COVID-19 pediatric patients and 5% among pediatric COVID-19 patients without AKI. However, data may be underestimated as the authors note that they used creatinine instead of urine output to define AKI [12]. The most common clinical features of COVID-19 among children include fever, dry cough, and pneumonia, along with an increasing prevalence of multisystem dysfunction [26]. Within the 2,596 pediatric COVID-19 cohort from the VPS data from North American PICU's, several additional organ systems were reportedly involved including 49.3% of patients with respiratory symptoms, 33.1% with circulatory symptoms, 21.6% with digestive/excretory symptom, 17.6% with hematologic symptoms, 12.3% with neurologic symptoms, and 11.7% with kidney/ urinary symptom. Correspondingly, comorbidities that were reported to be significantly higher among the VPS AKI-group as opposed to the non-AKI group included respiratory  22.6%]. In many COVID-19 cases, residual renal impairment may be attributed to the systemic effects of decreased tissue perfusion from hypoxia or transient periods of hypotension, fluctuations in electrolyte levels or hypernatremia, and/or associated comorbidities [13]. Consequently, physicians ought to be aware of such factors that may precipitate renal complications in COVID-19 patients. Ultimately, research aims to improve short-term outcomes as measured by hospital LOS along with overall long-term outcomes in quality of life.
Despite COVID-19's potential severity, studies have suggested that children are less susceptible than adults. Lee et al. theorizes that this is because children have a more active innate immune response, are generally more protected by parents, engage in fewer outdoor activities, are less likely to travel internationally, and have relatively less comorbidities [29]. Biochemically, ACE2 demographics differ from its distribution, maturation, and function-ultimately affecting its association with the receptor binding domain of the COVID-19 spike-protein and reducing susceptibility and severity [6,29,30]. However, more studies are needed to fully elucidate why children are less susceptible than the adult population to severe COVID-19 infections.
Due to the retrospective database design of this study, there are notable limitations. This study is limited to data from a select number of pediatric ICUs across only North America, therefore limiting our ability to apply our results globally. Additionally, as COVID-19 continues to progress and new viral variants being to emerge, new advances in data and research will emerge, which will allow for better understanding of the virus.

Conclusion
Overall, AKI incidence among pediatric ICU patients was 10.8%, which is higher than multiple previous large-scale studies had described. AKI severity among children with COVID-19 has The mortality status and kidney support has been used in the classification of AKI stage, therefore these outcomes have not been considered for analysis. https://doi.org/10.1371/journal.pone.0266737.t004 additionally been shown to be associated with an increased risk of mortality. Despite the reduced susceptibility of severe disease in children, it is crucial to continue to develop the knowledge base surrounding all manifestations of COVID-19 among children across the world. A greater understanding of COVID-19 among the pediatric population may reduce the potential for exponentially increasing rates of morbidity and mortality through this highly transmissible virus.
Supporting information S1 File. Supporting information.